U.S. patent number 4,262,003 [Application Number 05/777,130] was granted by the patent office on 1981-04-14 for method and therapeutic system for administering scopolamine transdermally.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Kumar Chandrasekaran, Jane Shaw, John Urquhart.
United States Patent |
4,262,003 |
Urquhart , et al. |
April 14, 1981 |
**Please see images for:
( Certificate of Correction ) ** |
Method and therapeutic system for administering scopolamine
transdermally
Abstract
Method and therapeutic system in the form of a bandage that
administer scopolamine base transdermally in an initial pulse of 10
to 200 .mu.g/cm.sup.2 of skin that quickly brings the concentration
of scopolamine in the plasma to a level at which emesis and nausea
are inhibited without intolerable side effects, followed by a
substantially constant dosage in the range of 0.3 to 15 .mu.g/hr
that holds said level. The bandage is a four-layer laminate of,
from the top: a protective backing; a gelled, mineral
oil-polyisobutene-scopolamine reservoir lamina that is the source
of the constant dosage; a microporous membrane that controls the
constant dosage rate; and a gelled, mineral
oil-polyisobutene-scopolamine adhesive layer that is the source of
the pulse dose and the means by which the bandage is attached to
the skin.
Inventors: |
Urquhart; John (Palo Alto,
CA), Chandrasekaran; Kumar (Palo Alto, CA), Shaw;
Jane (Atherton, CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
27093220 |
Appl.
No.: |
05/777,130 |
Filed: |
March 14, 1977 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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721602 |
Sep 7, 1976 |
4031894 |
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638947 |
Dec 8, 1975 |
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547504 |
Feb 6, 1975 |
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Current U.S.
Class: |
514/291;
514/872 |
Current CPC
Class: |
A61K
31/46 (20130101); A61F 13/00063 (20130101); A61F
13/8405 (20130101); A61F 13/534 (20130101); A61F
2013/00902 (20130101); A61F 2013/53445 (20130101); Y10S
514/872 (20130101) |
Current International
Class: |
A61F
13/00 (20060101); A61K 31/46 (20060101); A61F
13/15 (20060101); A61K 031/445 () |
Field of
Search: |
;424/267 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Clin. Pharmacol Ther. 11, 621-627 (1970)..
|
Primary Examiner: Waddell; Frederick E.
Attorney, Agent or Firm: Ciotti; Thomas E. Sabatine; Paul L.
Mandell; Edward L.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This is a division, of application Ser. No. 721,602, filed Sept. 7,
1976, now U.S. Pat. No. 4,031,894, and is a continuation-in-part of
Ser. No. 638,947 filed Dec. 8, 1975, now abandoned which in turn is
a continuation-in-part of Ser. No. 547,504 filed Feb. 6, 1975, now
abandoned .
Claims
What is claimed is:
1. Method for inhibiting emesis and nausea for a prolonged time
period comprising administering scopolamine base to unbroken skin
in an initial pulse of about 10 to about 200 .mu.g/cm.sup.2 of skin
and thereafter at a substantially constant rate in the range of
about 0.3 to about 15 .mu.g/hr for as long as therapy is
required.
2. The method of claim 1 wherein the emesis and nausea arre induced
by a vestibular disturbance and the administration begins at least
about 3 hr before the disturbance requires therapy.
3. The method of claim 1 wherein the total quantity of scopolamine
base administered is in the range of 0.1 to 2.5 mg.
4. The method of claim 1 wherein the skin is located at the
mastoidal area.
5. The method of claim 1 wherein the skin is at a body site other
than a mastoidal area and the skin is treated with an effective
amount of a skin permeation enhancing agent.
6. The method of claim 5 wherein the skin permeation enhancing
agent is selected from the group consisting of dimethyl lauramide,
dimethyl sulfoxide, and dodecyl pyrrolidone.
7. The method of claim 1 wherein the initial pulse is about 50 to
about 150 .mu.g/cm.sup.2 of skin and the substantially constant
rate is about 5 to 15 .mu.g/hr for adults and 3 to 10 .mu.g/hr for
children.
8. A method of claim 7 wherein the skin is located at a mastoidal
area.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is a method for administering scopolamine
transdermally to inhibit emesis and nausea and a therapeutic system
in the form of a bandage structured specifically to carry out the
method.
2. Description of the Prior Art
There are several patents that relate to bandages for administering
systemic drugs transdermally. In this regard, U.S. Pat. No.
3,797,494 is believed to be the most relevant to the present
invention. FIG. 2 of that patent shows a bandage that includes the
basic elements of the invention bandage. Indeed, the invention
bandage is considered to be a patentable embodiment of the bandage
depicted in said FIG. 2. Both bandages are laminates that include a
backing, a drug reservoir, a microporous membrane and a contact
adhesive layer. However, scopolamine is present in the invention
bandage in specific proportions in the contact adhesive layer as
well as in the reservoir. Also, the matrix of the reservoir layer
of the invention bandage is a gel.
The antiemetic and antinauseant properties of scopolamine and
related compounds are known. These properties have been
investigated by administering scopolamine and related compounds
intramuscularly and orally..sup.1
Scopolamine acid salts and the C.sub.4 -C.sub.12 esters of
scopolamine have been applied topically as antiperspirants. The
C.sub.4 -C.sub.12 scopolamine esters are reported to be more
effective antiperspirants than scopolamine itself because they
penetrate better. These esters are the subject of U.S. Pat. No.
3,767,786. They were tested as antiperspirants by applying them as
solutions or creams to the forearm and axilla at a dose of 2 mg.
Minor systemic responses were observed. Such responses were
correlated with systemic responses obtained by administering the
esters subcutaneously and it was estimated therefrom that only 5%
to 10% of the dermally applied esters was absorbed.
The above mentioned patent suggests using mineral oil as a vehicle
for antiperspirant compositions containing the esters, provided
there is sufficient water miscible vehicle also present to provide
a medium for absorption by the skin. Various surfactants are
reported as absorption enhancers for the scopolamine esters.
SUMMARY OF THE INVENTION
The invention is a method for administering scopolamine base
transdermally to inhibit emesis and nausea for a prolonged time
without evoking intolerable side effects, and a therapeutic system,
in the form of a bandage, by which the method may be practiced.
This therapeutic system incorporates the scopolamine in a
programmed dosage form that administers the scopolamine at a
predetermined rate over an extended time period.
Specifically, the method comprises administering scopolamine base
to unbroken skin in an initial pulse of about 10 to about 200
.mu.g/cm.sup.2 of skin, and thereafter at a substantially constant
rate of about 0.3 to 15 .mu.g/hr until a total of about 0.1 to
about 2.5 mg scopolamine base have been administered. The bandage
for carrying out the above described method comprises a
sandwich-type laminate comprising: a backing layer that is
substantially impermeable to scopolamine base, one face of which
forms the top of the bandage, a scopolamine reservoir layer
adjacent to the opposite face of the backing layer comprising about
0.2 to about 3 mg scopolamine base dispersed in a gelled mixture of
mineral oil of about 10 to about 100 cp at 25.degree. C. and
polyisobutene; a microporous membrane layer adjacent and below the
scopolamine reservoir layer through which scopolamine is released
from the reservoir layer at a substantially constant rate in the
range of about 0.3 .mu.g to about 15 .mu.g scopolamine base per
hour after the bandage is affixed to the skin; and a contact
adhesive layer adjacent and below the microporous membrane layer by
which the bandage is affixed to the skin comprising 10 to 200 .mu.g
scopolamine base per cm.sup.2 of effective surface area of the
bandage dispersed in a gelled mixture of said mineral oil and said
polyisobutene. The above range for the constant rate portion of
scopolamine administration represents the average scopolamine
release rate following the initial two hours of administration.
As used herein the term "effective surface area" means the surface
area of the bandage that contacts the skin and through which
scopolamine is administered to the skin. As used herein in
connection with describing the constant rate portion of the
invention method and the rate at which scopolamine is released from
said reservoir layer, the term "substantially" indicates that the
rate may vary .+-.30%. Such variation may be inherent in the
manufacturing procedure, or be caused by temperature fluctuation,
poor affixation of the bandage to the skin, and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawing is an enlarged, schematic, cross-sectional view of the
preferred embodiment of the bandage of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention resides in the discovery of how to administer
scopolamine transdermally to effectively inhibit nausea and emesis
without eliciting intolerable parasympatholytic side effects. It
involves delivering scopolamine base to the plasma in a controlled
manner according to a precise dosage program consisting of an
initial pulse administration followed by administration at a
substantially constant rate until a desired total quantity of
scopolamine has been administered.
Emesis and nausea may be induced by pregnancy, vestibular
disturbances (e.g., those caused by motion), radiation treatment,
drug treatment (e.g., cancer chemotherapy) or treatment with
anesthetics. Such illness may be inhibited by the method of this
invention.
The purpose of the pulse portion of the dosage program is to
shorten the time it takes for the scopolamine concentration in the
plasma to reach the level required for preventive therapy. It
partially does this by "saturating" the skin with scopolamine. In
this respect the skin initially acts as a "sink" rather than as a
"conduit", with most of the scopolamine being bound within the skin
and not passing through to circulation. However, once the skin is
"saturated", that is the binding sites are occupied, it permits
additional scopolamine to pass through circulation. Thus the amount
of scopolamine administered in the pulse is a function of the area
of skin being treated. A pulse of 10 to 200 .mu.g scopolamine per
cm.sup.2 of skin being teated will usually allow the therapeutic
level in the plasma to be reached within about 2-3 hr. Accordingly,
an adequate time margin of safety is provided if administration is
begun at least about 3 hr before illness is expected. In most
instances the pulse will be in the range of 50 to 150 .mu.g
scopolamine per cm.sup.2 of skin being treated. Alternatively the
pulse may be expressed in terms of the average release rate per
unit of effective surface area over the first two hours of
administration. Expressed in this manner in most instances the
pulse will be in the range of 20 to 60 .mu.g/hr/cm.sup.2. The
concentration of scopolamine in the plasma can be related to the
concentration of free scopolamine in the urine if the glomerular
filtration rate of the subject is known, and it is convenient to
express the quantity of scopolamine in the plasma in terms of a
urinary excretion rate. An average urinary excretion rate of about
0.3 .mu.g free scopolamine per hr was found to generally correspond
to a therapeutic plasma level. However, it was also found that this
rate is subject to about a .+-.5%-fold biological variation.
Therefore, the rate ranges between about 0.05 and about 1.5 .mu.g
per hr depending on the individual.
The purpose of the substantially constant rate administration
portion of the method is to supplement, it necessary, the pulse
administration in delivering enough scopolamine to reach the above
mentioned therapeutic level and to hold that level for as long as
is necessary. It follows that the constant rate administration
portion will proceed for as long as therapy is required. In this
regard a total (including the pulse) of 0.1 to 2.5 mg scopolamine
administered in accordance with the above described dosage program
will provide a therapeutic effect for about 3 hours to 7 days. It
also follows that the level of constant rate administration may
vary depending on the body weight (plasma volume) of the patient.
In this regard in most instances the rate will be in the range of 5
to 15 .mu.g per hr for adults and 3 to 10 .mu.g per hr for children
(measured as the average rate after 2 hr of administration i.e.
after the initial 2 hr of pulse administration).
The skin location at which the method is carried out is important
for the reliability and reproducibility of the method. This is
because the histology, thickness and vascularization of skin varies
from individual to individual as well as from body site to body
site on a given individual, and such variance affects the efficacy
with which scopolamine may be delivered to the plasma. Applicants
have found that the effect of this variance may be substantially
eliminated in either of two ways. The first way is to carry out the
method at a skin site, namely the mastoidal area, where scopolamine
permeation does not vary significantly from individual to
individual and thus the quantity of scopolamine delivered to the
plasma or the rate at which such delivery is made is not
significantly different between individuals. The second way is to
eliminate the stratum corneum as a quantity-affecting or
rate-affecting element by treating the skin at the administration
site with a skin permeation enhancing agent. Such treatment will
allow the method to be carried out at body sites, such as the arms,
legs or torso, other than the mastoidal area. Depending on the
particular agent involved, the treatment may occur prior to or
simultaneously with the administration of scopolamine base pursuant
to the invention method. Likewise, the quantity of agent needed
will depend on the particular agent used. In any event, the agent
plays the dual role of increasing the permeability of the stratum
corneum to scopolamine and decreasing the tendency of the stratum
corneum to bind scopolamine. Examples of known agents which may be
used are dodecyl pyrrolidone, dimethyl lauramide and dimethyl
sulfoxide. All three of these agents may be used in pre-treatment
applications. The pyrrolidone and lauramide may be applied to the
administration site at about 4 to 8 mg/cm.sup.2 for approximately
an hour and then washed off. They may be administered
simultaneously with the scopolamine at approximately the same
dosage as the scopolamine. The sulfoxide is preferably used only as
a pre-treatment at doses in the range of 5 to 100 mg/cm.sup.2 for
approximately one hour, and then washed off.
The drawing depicts a bandage, generally designated 10, that when
applied to skin administers scopolamine base according to the
prescribed dosage program. Bandage 10 is a five-layer laminate. The
top layer 11 is a backing that is substantially impermeable to
scopolamine base. Its face 12 forms the top surface of the bandage.
Backing 11 serves as a protective covering, keeps the volatile
components of the bandage from escaping, and fulfills a support
function. Preferably, backing layer 11 is itself a laminate of
films of polymer and metal foil such as aluminum foil. Polymers
that may be used in the layer are high and low density
polyethylene, polypropylene, polyvinylchloride and polyethylene
terephthalate.
Below and adjacent to layer 11 is a scopolamine reservoir layer 13.
Layer 13 contains about 1 to about 6 mg scopolamine base, the
undissolved portion of which is depicted as droplets 14. The
scopolamine base contained in layer 13 is delivered to the plasma
during the constant administration portion of the invention method.
Droplets 14 are dispersed homogeneously in a gelled mixture of
mineral oil of about 10 to about 100 cp at 25.degree. C. and a
blend of polyisobutene. The oil will usually constitute 35% to 65%
by weight of the mixture and the polyisobutene will correspondingly
usually constitute 35% to 65% by weight of the mixture. The
polyisobutene blend comprises a low molecular weight polyisobutene
(35,000-50,000 viscosity average molecular weight) and a high
molecular weight polyisobutene (1,000,000-1,500,000 viscosity
average molecular weight). Preferred mixtures comprise 35% to 65%
mineral oil, 10% to 40% low molecular weight polyisobutene, and 20%
to 40% high molecular weight polyisobutene. These oil-polyisobutene
mixtures are excellent adhesives and help to hold the bandage
together. If they were not good adhesives, other means, such as
heat sealing, would have to be used to keep the bandage
together.
The mineral oil in layer 13 functions as a carrier for the
scopolamine base. Scopolamine base has limited solubility in the
mineral oil (approximately 2 mg/ml) and the relative amounts of
each in layer 13 are such that the mineral oil is saturated with
the base for essentially the entire dispensing lifetime of the
bandage.
The next lamina in the bandage is a microporous membrane 15 whose
pores are filled with the above described mineral oil. Membrane 15
is the element of the bandage that controls the rate at which the
base is released from layer 13. The flux of scopolamine through
membrane 15 and the area of membrane 15 must be such that
scopolamine is released from reservoir layer 13 to the skin at a
sutstantially constant rate in the range of 0.3 to 15 .mu.g/hr
after the bandage has been put in use. The flux follows Fick's law.
It is a function of the tortuosity, porosity and thickness of the
membrane, the concentration gradient of scopolamine base across the
membrane and the diffusion coefficient of scopolamine base in the
mineral oil. The concentration gradient depends on the scopolamine
concentrations in the mineral oil at the opposite sides of the
membrane. The diffusion coefficient depends on the mineral oil
viscosity and decreases with increasing viscosity. The three
properties of the membrane are, of course, constant for any given
membrane. Membranes that have porosities from about 0.1 to 0.85,
tortuosities from 1 to 10, and thicknesses from 10.sup.-3 to
10.sup.-2 cm may be used. The membrane may be formed from polymers
such as polypropylene, polycarbonates, polyvinylchloride, cellulose
acetate, cellulose nitrate, and polyacrylonitrile.
Below and adjacent membrane 15 is a contact adhesive lamina 16.
Lamina 16 contains 10 to 200 .mu.g scopolamine base per cm
effective surface area. The undissolved portion of the scopolamine
is depicted as droplets 17. The scopolamine base in lamina 16 is
the pulse dosage of the invention method. The scopolamine is
dispersed in the same mineral oil-polyisobutene mixture that is
used in layer 13. Lamina 16 is the means by which the bandage is
attached to the skin. In this regard the mineral oil-polyisobutene
mixture adheres less strongly to skin than it does to the other
laminas of the bandage; therefore, the bandage tends to remain
intact when it is pulled off the skin.
Prior to use, the bandage also includes a strippable, protective
coating 18 that covers lamina 16. Just prior to use, the coating 18
is peeled away from lamina 16 and discarded. It may be made from
scopolamine-mineral oil impermeable materials such as the polymers
from which backing 11 may be made, with the provision that these
materials are made strippable, such as by siliconizing.
Bandage 10 may be applied to either mastoidal region and it will
administer scopolamine according to the described dosage program
without requiring any prior or simultaneous treatment of the region
with a skin permeation enhancing agent. As indicated above, if the
bandage is applied to a body site other than a mastoidal area, the
site should be treated with one or more of the described skin
permeation enhancing agents. If simultaneous treatment is desired,
the agent may be incorporated into bandage 10. In that instance,
layers 13 and 16 will contain effective quantities of such
agents.
The size of the bandage is not critical. The bandage will usually
be sized to administer scopolamine to an area of skin in the range
of 0.5 to 4 cm.sup.2. Correlatively, the effective surface area of
the bandage will also usually be in the range of 0.5 to 4 cm.
EXAMPLES
The following examples illustrate the invention. They are not
intended to limit the scope of the invention in any way. Unless
indicated otherwise, parts are by weight.
EXAMPLE 1
A solution of 29.2 parts high molecular weight polyisobutene (sold
under the designation Vistanex MML-100, 1,200,000 viscosity average
molecular weight), 36.5 parts low molecular weight polyisobutene
(sold under the designation Vistanex LM-MS, 35,000 viscosity
average molecular weight), 58.4 parts mineral oil (10 cp at
25.degree. C.), 15,7 parts scopolamine base and 860.2 parts
chloroform is solvent cast onto an approximately 65 micron thick
backing film of aluminized polyethylene terephthalate (sold under
the designation MEDPAR) to form a scopolamine base reservoir layer
approximately 50 microns thick. A contact adhesive layer-strippable
coating combination is similarly prepared by solvent casting onto a
200 micron thick siliconized, aluminized, polyethylene backed
polyethylene terephthalate film a solution of 31.8 parts of said
high molecular weight polyisobutene, 39.8 parts of said low
molecular weight polyisobutene, 63.6 parts of said mineral oil, 4.6
parts of scopolamine base and 860.2 parts chloroform. The resulting
contact adhesive layer is approximately 50 microns thick.
The above described backing-reservoir layer combination is then
laminated to one face of a 25 micron thick microporous
polypropylene membrane (sold under the designation Celgard 2400)
saturated with said mineral oil and the above described contact
adhesive layer-strippable coating combination is laminated to the
opposite face of the membrane. One cm.sup.2 circular, disc-shaped
bandages are punch cut from the resulting 5-layer laminate. Each
bandage is designed to release an initial 150 .mu.g/cm.sup.2 pulse
of scopolamine followed by an essentially constant dosage of 3-3.5
.mu.g/cm.sup.2 /hr.
EXAMPLE 2
A solution of 22.3 parts of the high molecular weight polyisobutene
described in Example 1, 28.0 parts of the low molecular weight
polyisobutene described in Example 1, 44.9 parts mineral oil (66 cp
at 25.degree. C.), 12.8 parts scopolamine base, 8.8 parts dimethyl
lauramide and 883.2 parts of chloroform is solvent cast onto the
backing film described in Example 1 to form a scopolamine base
reservoir layer approximately 50 microns thick. A contact adhesive
layer-strippable coating combination is similarly prepared by
solvent casting onto the siliconized polyethylene terephthalate
film described in Example 1 a solution of 23.5 parts of said high
molecular weight polyisobutene, 29.5 parts of said low molecular
weight polyisobutene, 47.6 parts mineral oil (66 cp at 25.degree.
C.), 7.8 parts scopolamine base, 9.0 parts dimethyl lauramide and
882.6 parts chloroform. The resulting contact layer is
approximately 50 microns thick.
The above-described backing-reservoir layer combination is then
laminated to one face of a 25 micron thick microporous
polypropylene membrane (sold under the designation Celgard 2400)
saturated with said mineral oil and the above described contact
adhesive layer-strippable coating combination is laminated to the
opposite face of the membrane. Four cm.sup.2 circular, disc-shaped
bandages are punch cut from the resulting 5-layer laminate. Each
bandage is designed to release an initial 125 .mu.g/cm.sup.2 pulse
of scopolamine followed by an essentially constant dosage of 2
.mu.g/cm.sup.2 /hr.
The bandages of Examples 2 were tested on a double blind basis as
follows. A bandage was applied to the skin behind the ear of 17
subjects prior to exposure to motion at sea. Placebo bandages (no
scopolamine present) were similarly applied to 18 subjects. All
subjects had a prior history of experiencing motion-induced nauses.
Only one of the 17 subjects wearing the bandages of Example 2
became ill to the extent that additional antinauseant medication
had to be administered while at sea. In contrast, 9 of the subjects
wearing the placebo bandages had to receive additional antinauseant
medication while at sea.
EXAMPLE 3
Therapeutic systems were made according to the procedure of Example
1 except that: the strippable coating was 127 micron thick
siliconized polyethylene terephthalate film and the systems were
each 2.5 cm.sup.2 in area. In vitro tests of these systems showed
they released an initial pulse of approximately 200 .mu.g in the
first two hours of use and an average of approximately 10 .mu.g/hr
thereafter through 72 hr.
Modifications of the above described method and therapeutic systems
that are obvious to persons of skill in the medical, chemical
and/or pharmaceutical arts are intended to be within the scope of
the following claims.
* * * * *